Clinical Review & Education
Neuroscience and Psychiatry
Neuroprotective Effects of Prenatal Folic Acid Supplementation
Why Timing Matters
Joshua L. Roffman, MD, MMSc
Neurodevelopmental theories of autism, schizophrenia, and other
brain disorders implicate the fetal environment.1 Although certain
toxic exposures during pregnancy (eg, infection, malnutrition, and
urbanicity) have been repeatedly associated with disease risk, spe-
cific etiologic mechanisms remain unclear. However, alterations in
the fetal methylation milieu are likely of central importance.
Methylation reactions contribute directly to DNA synthesis and
are thus essential to central nervous system development. Further-
more, methylation of histones and DNA regulates gene expression
in fetal and postnatal life.2 Although DNA methylation fluctuates
greatly during fetal development, methylation marks from late in ges-
tation tend to be enduring.3 As such, they could influence expres-
sion of risk-relevant genes during or long after fetal development.1
However, identification of specific fetal epigenetic patterns that un-
derlie neuropsychiatric risk is challenging for numerous reasons,
chiefly our inability to measure and manipulate such patterns di-
rectly in living human fetal brains and the difficulty of associating fe-
tal exposure with risk of illness years later.
That said, quasi-experimental, population-based studies of pre-
natal folic acid exposure offer largely untapped potential to probe
how variation in the fetal methylome influences disease risk. Fo-
late, an essential B vitamin found in leafy green vegetables, citrus,
and lentils, supplies 1-carbon (methyl) moieties that drive methyla-
tion reactions in the body. A synthetic and more highly bioavailable
form of folate, folic acid, is found in vitamin supplements and in some
enriched grain products. Studies in the 1980s conclusively linked low
maternal folate levels early in pregnancy with the risk for spina bi-
fida and other neural tube defects (NTDs). Based on this evidence
and that such defects occur before many pregnancies are recog-
nized, all women of childbearing age are broadly recommended to
consume daily folic acid through vitamin supplements. Further-
more, 81 countries now mandate folic acid fortification of enriched
grain products. In the United States, this intervention (introduced
in 1996) was associated with both reduced NTD incidence and, more
broadly, a rapid doubling of blood folate levels in women of child-
bearing age.4
However, variation in fortification exposure and timing of supple-
ment use are associated with variation in maternal folic acid intake.
Reasons for this variation are likely complex, reflecting patient and
clinician knowledge and a range of individual, practical, and geo-
graphic factors. Despite this heterogeneity, carefully conducted stud-
ies that associate prenatal folic acid intake with psychiatric out-
comes have produced impressive, if correlational, findings. Several
large, prospective cohort studies have associated periconcep-
tional use of folic acid supplements (ie, initiation of supplement use
before conception or within the first 8 weeks thereafter) with re-
ductions (nearly 50%) in the offspring’s subsequent risk for autism5
(although 1 study had null findings6). Conversely, replicated studies7
jamapsychiatry.com
© 2018 American Medical Association. All rights reserved.
Downloaded From: by a Université de Strasbourg User on 05/09/2018
demonstrated a transient doubling of schizophrenia incidence 2 de-
cades after prenatal exposure to famine. Although we cannot iso-
late specific causal factors from among many associated with star-
vation, the co-occurrence of NTDs in 1 such cohort suggests low
prenatal folate levels as a parsimonious explanation.7 Further-
more, studies of folic acid supplementation in adult patients with
schizophrenia8 have demonstrated modest clinical benefit, al-
though with effect sizes smaller than in prenatal studies.
This work raises important questions about how and when fo-
lic acid may protect against neurodevelopmental disorders. For
NTDs, a plausible explanation relates to the dependence of neuro-
epithelium that overlies the neural tube, which closes around preg-
nancy day 28, on 1-carbon moieties for DNA synthesis. However, it
is curious and somewhat counterintuitive that periconceptional
(rather than later) folic acid supplement use should influence risk for
autism and potentially schizophrenia. These disorders are charac-
terized by subtle, primarily microscopic abnormalities in brain struc-
ture and function. However, development of brain tissue in the first
2 months of pregnancy is comparably primitive, largely consisting
of proliferation and migration of neural progenitor cells; disruption
of this process results in gross abnormalities that are frequently in-
compatible with life. Resolving this apparent contradiction could pro-
vide opportunities not only to substantiate epidemiologic correla-
tions with underlying mechanisms but also to discover new avenues
for early intervention.
One potential explanation for this temporal discrepancy, pro-
posed herein, relates to the association of pregnancy with mater-
nal folate levels (Figure). Before the supplementation era, it was ob-
served that fetal demand for DNA synthesis and chromatin
methylation throughout pregnancy dramatically reduced maternal
folate levels, which are lowest at childbirth.9 Furthermore, studies
of sequential folate depletion and repletion in young women10 in-
dicate that recovery of serum folate levels takes weeks to months
to achieve. Even with periconceptional exposure to fortification
and/or folic acid supplementation initiated later in the first trimes-
ter, the delayed recovery of maternal folate levels may be insuffi-
cient to protect against risk for the more subtle developmental ab-
normalities of schizophrenia and autism (eg, in arborization and
cortical specialization), which likely occur late in pregnancy. In con-
trast, periconceptional supplements may provide sufficient re-
serves to protect against both NTDs and neuropsychiatric risk.
Although this and other mechanistic hypotheses remain un-
proven, this knowledge gap need not delay additional clinical and
epidemiologic studies of prenatal folic acid levels and neuropsychi-
atric risk. For example, monitoring incidence of severe mental ill-
ness will be of interest in coming years as the first cohort of youth
exposed to mandatory folic acid fortification in utero now ap-
proach the age of greatest risk for these illnesses.
(Reprinted) JAMA Psychiatry Published online May 9, 2018 E1
 Clinical Review & Education Neuroscience and Psychiatry

Figure. Maternal Folate Levels and Risk for Prenatal- vs Postnatal-Onset Disorders
of the Central Nervous System (CNS)

Periconceptional period

NTD risk period NDD risk period

(DNA replication) (DNA and histone methylation)

Low Low
Maternal Circulating Folate Level

Curves represent 4 different levels of

Fortification + folic acid exposure, their association
periconceptional with circulating folate levels
supplements
throughout pregnancy, and their
Fortification + potential relevance to prevention.
delayed Arrows indicate incremental
supplements association with fortification on
neural tube defect (NTD) risk

NDD risk
NTD risk

Fortification
(orange) and fortification alone (red),
High High No fortification fortification plus delayed
supplements (yellow), or fortification
Conception 1 2 3 4 5 6 7 8 9 plus periconceptional supplements
Time, mo (green) on neurodevelopmental
disorder (NDD) risk.

More broadly, leveraging fetal folic acid exposure to study
fetal methylomics provides an unusual opportunity to conduct
low-risk, potentially high-reward studies in human developmental
neuroscience. Overwhelming evidence suggests that recom-
mended doses of periconceptional folic acid supplements confer
minimal risk to the mother and fetus. As such, further studies of
any potential neuroprotective benefit, even if small, are easily jus-
tified, especially in light of the low cost and ready availability of
folic acid supplements. In addition, noninvasive, translational
studies of prenatal folic acid exposure and related epigenetic
changes (eg, using human stem cell models) may reveal molecu-
lar, cellular, and systems-level mechanisms through which fetal
methylation influences subsequent risk of brain disease. Such
work promises fundamental insights into prenatal brain develop-
ment and the possibility of preventing at least some cases of
severe mental illness in young people.

ARTICLE INFORMATION
Author Affiliations: Department of Psychiatry,
Massachusetts General Hospital, Charlestown;
Harvard Medical School, Boston, Massachusetts.
Corresponding Author: Joshua L. Roffman, MD,
MMSc, Department of Psychiatry, Massachusetts
General Hospital, 149 13th St, Room 2616,
Charlestown, MA 02129 (jroffman@partners.org).
Published Online: May 9, 2018.
doi:10.1001/jamapsychiatry.2018.0378
Conflict of Interest Disclosures: Dr Roffman
reported receiving consulting honoraria from
Pamlab for unrelated projects. No other disclosures
were reported.
Funding/Support: This study was supported by
grant R01MH101425 from the National Institute of
Mental Health (Dr Roffman).
Role of the Funder/Sponsor: The sponsor had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
REFERENCES
1. Bale TL, Baram TZ, Brown AS, et al. Early life
programming and neurodevelopmental disorders.
Biol Psychiatry. 2010;68(4):314-319.
2. Irwin RE, Pentieva K, Cassidy T, et al. The
interplay between DNA methylation, folate and
neurocognitive development. Epigenomics. 2016;8
(6):863-879.
3. Numata S, Ye T, Hyde TM, et al. DNA methylation
signatures in development and aging of the human
prefrontal cortex. Am J Hum Genet. 2012;90(2):
260-272.
4. Pfeiffer CM, Hughes JP, Lacher DA, et al.
Estimation of trends in serum and RBC folate in the
US population from pre- to postfortification using
assay-adjusted data from the NHANES 1988-2010.
J Nutr. 2012;142(5):886-893.
5. Surén P, Roth C, Bresnahan M, et al. Association
between maternal use of folic acid supplements
and risk of autism spectrum disorders in children.
JAMA. 2013;309(6):570-577.
6. Virk J, Liew Z, Olsen J, Nohr EA, Catov JM, Ritz
B. Preconceptional and prenatal supplementary
folic acid and multivitamin intake and autism
spectrum disorders. Autism. 2016;20(6):710-718.
7. Susser E, St Clair D. Prenatal famine and adult
mental illness: interpreting concordant and
discordant results from the Dutch and Chinese
Famines. Soc Sci Med. 2013;97:325-330.
8. Roffman JL, Lamberti JS, Achtyes E, et al.
Randomized multicenter investigation of folate plus
vitamin B12 supplementation in schizophrenia.
JAMA Psychiatry. 2013;70(5):481-489.
9. Ball EW, Giles C. Folic acid and vitamin B12 levels
in pregnancy and their relation to megaloblastic
anaemia. J Clin Pathol. 1964;17:165-174.
10. Shelnutt KP, Kauwell GP, Gregory JF III, et al.
Methylenetetrahydrofolate reductase 677C→T
polymorphism affects DNA methylation in response
to controlled folate intake in young women. J Nutr
Biochem. 2004;15(9):554-560.

E2 JAMA Psychiatry Published online May 9, 2018 (Reprinted) jamapsychiatry.com

© 2018 American Medical Association. All rights reserved.

Downloaded From: by a Université de Strasbourg User on 05/09/2018